1. Field of the Invention
The present invention is concerned with novel peptide compounds having long lasting LHRH agonist and antagonist activity, and with pharmaceutical compositions containing said novel peptide compounds, as well as their use in methods of promoting and methods of reducing fertility.
2. Brief Description of the Prior Art
Luteinizing hormone-releasing hormone (LHRH) is a neurohumoral hormone produced in the hypothalamus which stimulates the secretion of the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn produce changes resulting in the induction of ovulation. LHRH has the following structure: ##STR2##
Synthetic replicates of LHRH were readily available shortly after the primary sequence was disclosed in 1971 and, as a result, a sizable number of structural analogs of LHRH have been made and tested over the last few years. Some of these have proved to be more potent than LHRH as well as long-acting. See Rivier et al., Peptides 1976 (Proceedings of the Fourteenth European Peptide Symposium, Wepion, Belgium, Apr. 11-17, 1976), pp. 427-436. Thus, a D-amino acid has been utilized in the 6-position and/or N-methyl-Leu.sup.7 substitution has been made in order to obtain potent, long-acting LHRH agonists and antagonists. These prior studies have also indicated the importance of the backbone conformation to full potency of the analogs.
The novel peptides of the present invention, in contrast to the prior art, possess a five- or six-membered lactam bridge between the 6- and 7-positions of the peptide. It is theorized that this novel structure improves the biologically active (receptor bound) conformation of the peptide, thus affording greater potency, as well as the resistance of the peptide to enzyme degradation, thus extending the useful life of the peptide.
The novel peptides of the present invention are prepared in accordance with a novel process. Cyclizations of methionine sulfonium salts which have been previously reported have resulted in O-, rather than N-alkylation. See Yeung, et al., Biochemistry, Vol. 16, p. 1635 (1977).